1. Field of the Invention
The invention pertains to bioplastics for patient implantation or application, made at least in part from patient tissue or fluids such as plasma.
2. Description of Related Art
Fibrin-based plastics were invented in the 1940s as part of a U.S. Defense-sponsored research program to develop medical strategies for wounded military personnel. For example, fibrin-based plastics were developed out of the human blood program led by Edwin Cohn at Harvard University. John Ferry, then at Woods Hole, led the group that was involved in developing fibrin elastomers. As a result of this work, elastomeric sheet forms of fibrin were developed and used successfully in neurosurgical applications, burn treatments, and peripheral nerve regeneration. See, for example, Ferry, J.D. et al., Clin. Invest. 23:566-572 (1944); Bailey, O.T. et al, J. Clin. Invest. 23:597-600 (1944); Cronkite et al., JAMA, 124:976-8 (1944); and Ferry J.D. et al., Am. Chem. Soc J. 69:400-409 (1947). Hard fibrin plastics were fabricated into implants and were finding clinical success as early as the 1940s. See, for example, U.S. Pat. No. 1,786,488, No. 2,385,802, No. 2,385,803, No. 2,492,458, No. 2,533,004, No. 2,576,006, No. 3,523,807, No. 4,548,736, and No. 6,074,663, all incorporated herein by reference. Research sponsored by the Hungarian government led to the development of similar products in the 1950s through the early 1970s. Forms of hard plastic fibrin was demonstrated to have clinical efficacy in orthopedic applications of bone resurfacing. See, for example, Zinner, N. et al., Acta Med. Acad. Sci. Hung., 7:217-222 (1955); Gerendas, M., Ther. Hung., 7:8-16 (1959); and Gerendas, M., Chapter 13 in Fibrinogen, Laki, K., Ed., Marcel Dekker, New York, pp. 277-316 (1968).
Despite the efficacy of fibrin products, concerns about disease transmission from purified human fibrinogen from pooled plasma remained. However, during the late 1970s and thereafter, fibrin was developed as a tissue glue and sealant, and although this application required purified human fibrinogen, new techniques had been developed to ensure the safety of blood products. Consequently, fibrin-based glues and sealants have been used in clinical practice for over twenty years in Europe (and since 1998 in the United States) with no disease transmission concerns. Recently, the development of recombinant human fibrinogen and thrombin and purified salmon fibrinogen and thrombin have helped further to address concerns over both safety and market availability. See, for example, Butler S.P. et al., Transgenic Res. 13:437-450 (2004); Prunkard D. et al., Nat. Biotechnol. 4:867-871 (1996); Butler S. P. et al, “Thromb Haemost. 78:537-542 (1997); U.S. Pat. Nos. 5,527,692; 5,502,034; 5,476,777; 6,037,457; 6,083,902; and U.S. Pat. No. 6,740,736. Autologous sealants and glues are also available (see for example U.S. Pat. No. 6,979,307).
Despite such advances in the field, interest in the use of protein bioplastics in plastic forms, such as fibrin elastomers, has significantly declined over time. Silicone rubber sheets, which were introduced in the 1960s and 1970s, have replaced fibrin elastomeric sheets in the clinic, despite inherent problems with their permanence. There are also limitations with current synthetic bioresorbable plastics, such as polyurethane, polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), polyglycolic acid (PGA) and polycaprolactone. These polymers degrade in the body by hydrolysis, via bulk degradation, or through surface erosion, all of which operate independently of the surrounding biological environment. The inability of these polymers to degrade in response to cellular invasion and to promote directly the ingrowth of host tissues remains a profound limitation of bioresorbable implants.
In contrast, protein bioplastics can degrade in response to cellular proteolytic processes so that degradation occurs in concert with the growth and healing of host tissues. Also, many synthetic materials do not inherently bind growth factors of interest for therapeutic delivery options, whereas fibrin binds to growth factors directly and indirectly through molecular interactions with growth factors, including those with heparin binding domains. However, fibrin materials—including certain of the present inventors' own fibrin-based plastics based on purified fibrinogen/thrombin from pooled human or animal plasma—have certain constraints or limitations such as not inherently containing endogenous growth factors. Moreover, fibrin materials of the prior art are very expensive especially when prepared from human sources and with the required large amounts of starting material necessary to give desired yields. Commonly used synthetic materials, such as bioresorbable polymers, can be associated with inflammatory interactions, whereas these interactions would be less pronounced if one were to use protein-based plastics. Purified fish- or bovine-derived fibrinogen is potentially less expensive—although similar to its purified human counterpart in not containing human growth factors-yet disease transmission and immuno-sensitization with repeated use are potential major drawbacks due to its xenogenic source. Analogously to plastic implants, allogenic bone grafts also have several limitations, including high variability of graft quality from donor to donor. This variability arises from several factors including amount of active endogenous growth factors in each donated graft, and there are no practical means for quality assessment and/or quality control of allogenic bone graft materials with respect to these growth factors.
To date, methods and compositions previously developed for bioplastics, including but not limited to fibrin, elastin and etc., are not sufficiently adaptable for modern clinical use. For example, the original manufacturing methods developed for certain protein-based bioplastics required high temperatures (i.e., as high as 155° C.). Such high temperature processing precludes the use of exogenously added drugs and proteins as well as destroys any inherent biological activity. In addition, methods for making these materials porous have not been reported or developed previously. Prior to the present invention, no one had solved the problem of manufacturing bioplastics while avoiding the disadvantages of known processing techniques, such as high temperatures and pressures and/or difficulty in retaining desirable physical characteristics of the plastics. More importantly of all, perhaps, no one has heretofore addressed how effectively to reduce or eliminate the issues of disease transmission and immune response of bioplastics derived from animal or human pooled donor sources.
Therefore, certain needs remained prior to the present invention. Methods of incorporating heat-sensitive materials such as biological response modifiers, including but not limited to growth factors and extracellular matrix molecules, and drugs into elastomeric and/or pliant and/or hard materials were needed. Compositions having the ability to respond to the local cellular milieu were also needed, with or without spatial patterns in the overall construct or sheet to provided such responses where desired. Prior efforts to crosslink fibrin-based bioplastics were either post-fabrication methods, which generally created unwanted effects such as swelling, or used toxic crosslinking agents such as formaldehyde in addition to representing laborious processes. Fabrication methods were also needed that could be used to control properties of manufactured articles including for example the density, porosity, and mechanical properties of bioplastic materials. Methods of manufacturing biocompatible materials with anisotropic properties were needed, especially with regard to extrusion or directed strain and/or printing technologies to impart such anisotropic properties. For these and other reasons, more reliable, cost-effective substitute tissue graft materials including bioplastics have previously remained an illusive yet important clinical goal.